Tiotropium bromide, (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonane bromide or 6β, 7β-epoxy-3β-hydroxy-8-methyl-1αH, 5αH-tropanium bromide, di-2-thienylglycolate, has the following chemical structure:
It is an anticholinergic drug with specificity for muscarinic receptors. As a bronchodilator it provides therapeutic benefit in the treatment of asthma or chronic obstructive pulmonary disease (COPD). This active pharmaceutical ingredient is administered by inhalation, and is available commercially as SPIRIVA® HandiHaler®.
Tiotropium bromide was first disclosed in U.S. Pat. No. 5,610,163 where it was synthesized via N-demethyl tiotropium of formula III,
which was obtained by a reaction of methyl di(2-thienyl)glycolate of formula I and Scopine of formula II using sodium metal in melt or sodium methoxide in melt. Because of the dangerous reaction conditions, this method is not suitable for industrial scale preparation. The quaternization of N-demethyl-tiotropium is then carried out in a mixture of acetonitrile and methylene chloride using methyl bromide as a quaternizing agent. The process is illustrated in the following scheme:
The product was then crystallized from a mixture of acetone and methanol.
Also described in the prior art is the preparation of Scopine HCl, which was first disclosed in GB 1469781, wherein it was prepared by reduction of scopolamine using sodium borohydride, followed by addition of HCl to the reaction mixture, a process illustrated by the following scheme:
This salt of scopine can be used as a precursor for scopine base, however a process to remove inorganic salts from the desired product is not reported.
U.S. Pat. Nos. 6,486,321 and 6,506,900 disclose a synthesis of Tiotropium and analogues via tropenol derivatives by introducing an additional epoxidation step, as described by the following scheme.

U.S. Pat. No. 6,747,154, refers to formal approaches by stating “These processes known in the art may also be used to prepare the compounds of formula 1.

However, these methods of synthesis are more complex procedures involving a number of synthetic steps.” Therefore a different synthetic approach was developed, where the coupling is carried out using scopine methobromide rather than scopine, but details, including the yield, of this coupling reaction are not reported.

United States Patent Publication No 2006/0047120 describes yet another approach, coupling scopine methobromide with trimethylsilyl-protected sodium dithienyl glycolate which is obtained in situ.

This application, provides that this approach was developed to improve the prior art synthesis for Tiotropium bromide.
Hence, an improved process to prepare Tiotropium bromide is needed.